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Case Presentation: A 22-year-old male with a history of anti-neutrophil cytoplasmic antibody vasculitis, renal transplant, hypertension, and no known family history of sudden cardiac death suffered a witnessed cardiac arrest. An initial rhythm strip recorded by emergency medical services revealed ventricular fibrillation. Return of spontaneous circulation was achieved after three rounds of cardiopulmonary resuscitation, defibrillation, and intravenous epinephrine. The patient was brought to the emergency department and admitted to the intensive care unit. He was diagnosed with Brugada syndrome, and an automatic implantable cardioverter-defibrillator (AICD) was placed after discharge.Discussion: Brugada syndrome is characterized electrocardiographically by ≥2 millimeters (mm) ST-segment elevation in leads V1–V2 with either “coved type” (type 1) or “saddleback” (type 2) ST-segment morphology, or ≤2 mm ST-segment elevation in V1–V2 with either “coved” or “saddleback” morphology (type 3). The absence of these patterns on isolated electrocardiograms (ECG) does not exclude the diagnosis, as dynamic fluctuations in ECG patterns are well-documented and can be induced by various physiologic stressors. This case provides an uncommon, complete electrocardiographic history of Brugada syndrome, from out-of-hospital cardiac arrest to AICD placement and depicts dynamic fluctuations between Brugada patterns and normal ECGs. This highlights the importance of serial ECGs in diagnosis, as sudden cardiac death is often the first or only presentation of Brugada syndrome.

Background: Mutations in genes encoding desmosomal proteins are the leading cause of arrhythmogenic cardiomyopathy (ACM). The majority of the inherited ACM cases demonstrate autosomal dominant genotype. Several cases with the homozygous DSG2 c.1592T>G (p.F531C) variant genotype demonstrate adverse clinical outcomes, but the roles of associated genetic mutations are not clear. In this report, we describe three ACM cases with the homozygous DSG2 c.1592T>G (p.F531C) variant genotype combined with additional heterozygous cardiomyopathy-related genetic mutations that cause aggravated clinical manifestations and worse clinical outcomes. Case presentation: The three reported probands demonstrated similar clinical presentations such as heart failure, cardiac enlargement, and lethal arrhythmias. All of them experienced sudden cardiac death (SCD) before undergoing implantable cardioverter defibrillator (ICD) or heart transplantations. Wholeexome sequencing analysis demonstrated that the three patients inherited the homozygous DSG2 c.1592T>G (p.F531C) variant. Furthermore, probands I, II, and III also inherited additional heterozygous cardiomyopathy-associated mutations, including DSP c.7883T>C, SCN5a c.3577C>T, or MYH7 c.427C>T, respectively. These variants were confirmed as pathogenetic variants. A systematic review of all the reported ACM cases with the homozygous DSG2 variants suggested that the additional genetic mutations contributed to the early age onset of ACM and lethal cardiac events. Conclusion: In conclusion, we report three rare cases of ACM with the same homozygous DSG2 variant in combination with additional heterozygous mutations in cardiomyopathy-associated genes. A systematic review of all the ACM cases with homozygous DSG2 variants demonstrated that the additional genetic variants contributed to the aggravated clinical manifestations and worse clinical symptoms of the ACM patients because of homozygous DSG2 mutations, including early disease onset and lethal cardiac events. Our data suggested that comprehensive genetic evaluation should be performed to identify any potential additional pathogenic variants that may significantly influence the clinical prognosis and outcomes of patients with ACM. The knowledge of underlying molecular mutations would be useful in designing better therapeutic strategies for ACM patients with multiple genetic mutations. [ABSTRACT FROM AUTHOR]

Young (<18 years of age) patients with Brugada syndrome (BrS) are often under-represented in BrS studies and their management, especially related to syncopal episodes, remains unclear. This study sought to describe the arrhythmia prevalence among young patients with BrS undergoing continuous rhythm monitoring by implantable loop recorder (ILR) and to assess the etiology behind syncope of undetermined origin. A total of 147 patients with BrS with ILR were enrolled in 12 international centers and divided into pediatric (age <12 years; n = 77, 52%) and adolescents (age 13-18 years; n = 70, 48%). Mean age was 11.3 years, 53 patients (36.1%) were female, and 31 (21.1%) had spontaneous type 1 electrocardiograms. Over a median follow-up of 3.6 years (Q1-Q3: 1.6-4.8 years), an arrhythmic event was recorded in 33 patients (22.4%), mainly of nonventricular origin: 15 atrial (10.2%) and 16 bradyarrhythmic events (10.9%). Ventricular arrhythmias occurred in 4 patients, all with spontaneous BrS, and were fever-related in one-half. Among all patients with recurrence of syncope during follow-up, true arrhythmic syncope was documented in 5 (17.8%), and it was due to bradyarrhythmias or atrial arrhythmias in 3 cases (60%). Continuous rhythm monitoring with ILRs in young patients with BrS detects a broad range of arrhythmias. Ventricular arrhythmias occur predominantly in patients with spontaneous type 1 electrocardiograms and during fever. Despite the young age, bradyarrhythmias and atrial arrhythmias are frequent and represent the cause of arrhythmic syncope in 60% of patients. Young patients with BrS with syncope of undetermined origin may benefit from ILR implant. [ABSTRACT FROM AUTHOR]

Aims: Common genetic variations in the nitric oxide synthase‐1 adaptor protein (NOS1AP) gene are associated with QT‐interval prolongation. In a previous study, we observed an association between the rs10494366 variant of this gene and an increased QT‐interval shortening in digoxin users. As QT‐interval shortening is a risk factor for sudden cardiac death (SCD), in this study, we investigated whether the association between digoxin use and risk of SCD differs in participants with different NOS1AP rs10494366 genotypes. Methods: We included 11 377 individuals from the prospective population‐based cohort of the Rotterdam Study. We used Cox proportional hazard regression analysis with digoxin as time‐dependent exposure to estimate the associations between current digoxin use and the risk of SCD among different rs10494366 genotype groups in the adjusted models. We also studied whether such an association was dose‐dependent, comparing high dosage (≥ 0.250 mg), moderate dosage (0.125 mg ≤ dose< 0.250 mg) and low dosage (< 0.125 mg) digoxin users with non‐users. Results: The median baseline age of the total study population was 62 (interquartile range [IQR] 58–71) years. The cumulative incidence of SCD was 4.1% (469 cases), and among them, 74 (15.7%) individuals were current digoxin users at the time of death, during a median follow‐up of 11.5 (IQR 6.5–17) years. Current digoxin users had an increased risk of SCD (multivariable adjusted model hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 2.38–3.98), with no significant differences between the three genotype groups. The adjusted HRs were 4.03 [95% CI: 1.98–8.21] in the minor homozygous GG, 3.46 [95% CI: 2.37–5.04] in the heterozygous TG and 2.56 [95%CI: 1.70–3.86] in the homozygous TT genotype groups. Compared to low‐ and moderate‐dose, high‐dose digoxin users with GG genotype had the highest risk of SCD (HR: 5.61 [95% CI: 1.34–23.47]). Conclusions: Current use of digoxin is associated with a significantly increased risk of SCD. The NOS1AP gene rs10494366 variant did not modify the digoxin‐associated risk of SCD in a population of European ancestry. [ABSTRACT FROM AUTHOR]

High-risk coronary plaques (HRP) are characterized in clinical radiological imaging by the presence of low plaque attenuation, a napkin-ring sign (NRS), spotty calcifications (SC) and a positive remodeling index (RI). To evaluate if these signs are detectable in postmortem imaging by a multi-phase postmortem CT angiography (MPMCTA), a retrospective study of a series of autopsy well-documented coronary plaques related to sudden cardiac death (SCD) was performed. Then correlations between histological and radiological findings were described. Fourty SCD cases due to acute coronary syndrome based on clinical history and confirmed at autopsy were selected (28 men and 12 women, age 53.3 ± 10.9). The culprit lesion was mainly situated in the proximal segments of coronary arteries, in the right coronary artery in 23 cases (57.5%), the left anterior descending artery in 13 cases (32.5%), the circumflex artery in 3 cases (7.5%) and in one case in the left main stem. MPMCTA showed a positive RI (≥ 1.1) in 75% of cases with a mean RI 1.39 ± 0.71. RI values were lower in cases with fibrotic plaques. NRS was observed in 40% of cases, low attenuation plaque in 46.3%, and SC in 48.7% of cases. There were significant correlations of the radiological presence of NRS for fibrolipid composition of the plaque (p-value 0.007), severe intraplaque inflammation (p-value 0.017), severe adventitial inflammation (p-value 0.021) and an increased vasa vasorum (p-value 0.012). A significant correlation (p-value 0.002) was observed between the presence of SC at radiological examination and the presence of punctuate/fragmented calcification at histology. In addition, in 58.3% of cases, plaque enhancement was observed, which correlated with plaque inflammation and the fibrolipid composition of the plaque. The coronary artery calcium score was 314 (± 455). There was a poor agreement between stenosis of the lumen at histology versus radiology. Our study shows that the various radiological signs of HRP can be detected in all plaques by MPMCTA, but individually only to a variable extent; plaque enhancement appeared as a new sign of vulnerability. In the postmortem approach, these radiological markers of HRP, should always be applied in combination, which can be useful for developing a predictive model for diagnosing coronary SCD. [ABSTRACT FROM AUTHOR]

• Support groups offer a low-resource supportive care option for people with ICDs. • People with ICDs perceive benefit from sharing experiences and formal education. • Support groups may help people with ICDs return to normal activities post implant. • Support groups should be available before and after implant and not be time-limited. Support groups for people with Implantable Cardioverter Defibrillators (ICDs) are widely used, however, it is not clear what people with ICDs gain from a support group or what format they should take. The aim of the present study is to define the perceived benefit of ICD support groups and develop practical recommendations for group format. 14 individuals with ICDs were interviewed using a semi-structured interview guide. Reflexive thematic analysis methods were utilised to code and analyse the transcripts before generating themes. Four themes were defined: confronting mortality, coping through sharing, coping through learning, and providing space. Making connections with other people with ICDs, reassurance, access to information, and advice from health care professionals were important perceived benefits of the support group. People with ICDs may have to confront their own mortality and adapt to considerable life changes after implant. The findings from the present study have improved understanding of how support groups are perceived and how ICD indication and group format influence the experience. A blended format of in-person community meetings, online forums, HCP-led education and space for person-person interaction is recommended. Importantly, provision of support should not be time-limited to allow people to access it when it most likely to be of benefit to them. [ABSTRACT FROM AUTHOR]

Vitamin D is known to influence the risk of cardiovascular disease, which is a recognized risk factor for sudden cardiac arrest (SCA). However, the relationship between vitamin D and SCA is not well understood. Therefore, this study aims to investigate the association between vitamin D and SCA in out-of-hospital cardiac arrest (OHCA) patients compared to healthy controls. Using the Phase II Cardiac Arrest Pursuit Trial with Unique Registration and Epidemiologic Surveillance (CAPTURES II) registry, a 1:1 propensity score-matched case-control study was conducted between 2017 and 2020. Serum 25-hydroxyvitamin D (vitamin D) levels in patients with OHCA (454 cases) and healthy controls (454 cases) were compared after matching for age, sex, cardiovascular risk factors, and lifestyle behaviors. The mean vitamin D levels were 14.5 ± 7.6 and 21.3 ± 8.3 ng/mL among SCA cases and controls, respectively. Logistic regression analysis was used adjusting for cardiovascular risk factors, lifestyle behaviors, corrected serum calcium levels, and estimated glomerular filtration rate (eGRF). The adjusted odds ratio (aOR) for vitamin D was 0.89 (95% confidence interval [CI] 0.87–0.91). The dose-response relationship demonstrated that vitamin D deficiency was associated with SCA incidence (severe deficiency, aOR 10.87, 95% CI 4.82–24.54; moderate deficiency, aOR 2.24, 95% CI 1.20–4.20). Vitamin D deficiency was independently and strongly associated with an increased risk of SCA, irrespective of cardiovascular and lifestyle factors, corrected calcium levels, and eGFR. • Vitamin D's potential for reducing the risk of SCA remains uncertain despite cardiovascular diseases being a leading cause of SCA. • In this study, lower vitamin D levels were associated with SCA, showing a dose-response relationship. • The association remained after adjusting for eGFR, calcium, cardiovascular and lifestyle risk factors. [ABSTRACT FROM AUTHOR]

Myocarditis is a rare cardiomyocyte inflammatory process, typically caused by viruses, with potentially devastating cardiac sequalae in both competitive athletes and in the general population. Investigation into myocarditis prevalence in the Coronavirus disease 2019 (COVID-19) era suggests that infection with Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an independent risk factor for myocarditis, which is confirmed mainly through cardiovascular magnetic resonance imaging. Recent studies indicated that athletes have a decreased risk of myocarditis after recent COVID-19 infection compared to the general population. However, given the unique nature of competitive athletics with their frequent participation in high-intensity exercise, athletes possess distinct factors of susceptibility for the development of myocarditis and its subsequent severe cardiac complications (e.g., sudden cardiac death, fulminant heart failure, etc.). Under this context, this review focuses on comparing myocarditis in athletes versus non-athletes, owing special attention to the distinct clinical presentations and outcomes of myocarditis caused by different viral pathogens such as cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, human immunodeficiency virus, and Parvovirus B19, both before and after the COVID-19 pandemic, as compared with SARS-CoV-2. By illustrating distinct clinical presentations and outcomes of myocarditis in athletes versus non-athletes, we also highlight the critical importance of early detection, vigilant monitoring, and effective management of viral and non-viral myocarditis in athletes and the necessity for further optimization of the return-to-play guidelines for athletes in the COVID-19 era, in order to minimize the risks for the rare but devastating cardiac fatality. [ABSTRACT FROM AUTHOR]

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Copyright of Herzschrittmachertherapie und Elektrophysiologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background Methods Results Conclusions Conventional transvenous implantable cardioverter‐defibrillator (TV‐ICD) is the standard device used for primary prevention of sudden cardiac death (SCD) in patients with reduced left ventricular ejection fraction (LVEF). Nonetheless its use is associated with lead‐related complications including infection and malfunction. A subcutaneous implantable cardioverter‐defibrillator (S‐ICD) offers an alternative option without the need for a transvenous lead but has limitations. The decision to implant a TV‐ICD or S‐ICD in patients with impaired LVEF for primary prevention of SCD is controversial. Several randomised controlled trials and large observational studies have confirmed similar safety and efficacy of S‐ICDs and TV‐ICDs in such population.A literature review was conducted to compare the outcomes of subcutaneous (S‐ICD) versus transvenous (TV‐ICD) implantable cardioverter‐defibrillators. Databases including PubMed, MEDLINE, and Cochrane were searched for relevant peer‐reviewed articles. Studies were selected based on relevance and quality. Key outcomes like complication rates, efficacy, and patient survival were summarized in a comparative table.Different factors that influence the choice between an TV‐ICD and S‐ICD for primary prevention of SCD in patients with LVEF are highlighted to guide selection of the appropriate device in different patient populations. Moreover, future perspective on the combination of SICD with leadless pacemaker, and the latest development of the extravascular implantable cardioverter defibrillator are also discussed.S‐ICD offers a safe and efficacious option to primary prevention in reduced ejection fraction. Future development including incorporation of leadless pacemaker will add to the arsenal of choice to protect patients from sudden cardiac death. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Implantable Cardioverter Defibrillator (ICD) implantation has significantly modified the natural history of patients at high risk of sudden cardiac death (SCD) in various types of heart diseases. However there is a high rate of psychological distress and reduced quality of life in patients with an ICD, more evident in younger individuals. The ICD removal upon patient request is a very rare event and causes many clinical and ethical issues.The article discusses the case of a young patient affected by hypertrophic obstructive cardiomyopathy, who underwent implantable cardioverter defibrillator (ICD) implantation as a primary prevention of sudden cardiac death (SCD). Two years after the implantation, the patient repeatedly requested removal of the ICD due to of a significant and untreatable psychological device intolerance.Intervention became possible only after extensive psychological evaluation, which excluded specific pathology, and the ratification of Italian law 219/2017 on informed consent and advance directives, which guarantees the patient's independent decisions on current and future medical treatment. The explantation was performed 7 years after the implant. The patient is alive and in good health.The paper debates the issues related to establishing a patient–physician relationship based on respect for the patient's autonomy and experience of illness, in reference to principles such as beneficence and non‐maleficence, and the conflicts that sometimes arise between them.If a paternalistic approach in the patient–physician relationship evolves into a patient‐centered model, it is more certain that the patient's choice is realistically known and shared, and that it is consistent with the patient's values and life goals.The shared decision making (SDM) process and the use of pathology‐specific decision aids are able to transform the informed consent tool, usually related to medical‐legal issues, into an aid for true partnership between the patient and the medical care team. [ABSTRACT FROM AUTHOR]

Background and Aims Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. Methods Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c -statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). Results In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6–7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1–3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1–2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1–1.4)], LVEF < 50% [HR 1.5 (95% CI:.95–2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9–12.5)]. The model demonstrated good risk discrimination within both the development [ c -statistic.782 (95% CI:.77–.80)] and external validation [ c -statistic.791 (95% CI:.75–.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. Conclusions The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach. [ABSTRACT FROM AUTHOR]

Key points Arrhythmogenic cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes, which accounts for most cases of stress‐related arrhythmic sudden death, in young and athletes. AC hearts display fibro‐fatty lesions that generate the arrhythmic substrate and cause contractile dysfunction. A correlation between physical/emotional stresses and arrhythmias supports the involvement of sympathetic neurons (SNs) in the disease, but this has not been confirmed previously. Here, we combined molecular, in vitro and ex vivo analyses to determine the role of AC‐linked DSG2 downregulation on SN biology and assess cardiac sympathetic innervation in desmoglein‐2 mutant (Dsg2mut/mut) mice. Molecular assays showed that SNs express DSG2, implying that DSG2‐mutation carriers would harbour the mutant protein in SNs. Confocal immunofluorescence of heart sections and 3‐D reconstruction of SN network in clarified heart blocks revealed significant changes in the physiologialc SN topology, with massive hyperinnervation of the intact subepicardial layers and heterogeneous distribution of neurons in fibrotic areas. Cardiac SNs isolated from Dsg2mut/mut neonatal mice, prior to the establishment of cardiac innervation, show alterations in axonal sprouting, process development and distribution of varicosities. Consistently, virus‐assisted DSG2 downregulation replicated, in PC12‐derived SNs, the phenotypic alterations displayed by Dsg2mut/mut primary neurons, corroborating that AC‐linked Dsg2 variants may affect SNs. Our results reveal that altered sympathetic innervation is an unrecognized feature of AC hearts, which may result from the combination of cell‐autonomous and context‐dependent factors implicated in myocardial remodelling. Our results favour the concept that AC is a disease of multiple cell types also hitting cardiac SNs. Arrhythmogenic cardiomyopathy is a genetically determined cardiac disease, which accounts for most cases of stress‐related arrhythmic sudden death. Arrhythmogenic cardiomyopathy linked to mutations in desmoglein‐2 (DSG2) is frequent and leads to a left‐dominant form of the disease. Arrhythmogenic cardiomyopathy has been approached thus far as a disease of cardiomyocytes, but we here unveil that DSG2 is expressed, in addition to cardiomyocytes, by cardiac and extracardiac sympathetic neurons, although not organized into desmosomes. AC‐linked DSG2 downregulation primarily affect sympathetic neurons, resulting in the significant increase in cardiac innervation density, accompanied by alterations in sympathetic neuron distribution. Our data supports the notion that AC develops with the contribution of several ‘desmosomal protein‐carrying’ cell types and systems. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion To assess whether left ventricular (LV) global longitudinal strain (GLS), derived from cardiovascular magnetic resonance (CMR), is associated with (i) progressive heart failure (HF), and (ii) sudden cardiac death (SCD) in patients with dilated cardiomyopathy with mildly reduced ejection fraction (DCMmrEF).We conducted a prospective observational cohort study of patients with DCM and LV ejection fraction (LVEF) ≥40% assessed by CMR, including feature‐tracking to assess LV GLS and late gadolinium enhancement (LGE). Long‐term adjudicated follow‐up included (i) HF hospitalization, LV assist device implantation or HF death, and (ii) SCD or aborted SCD (aSCD). Of 355 patients with DCMmrEF (median age 54 years [interquartile range 43–64], 216 men [60.8%], median LVEF 49% [46–54]) followed up for a median 7.8 years (5.2–9.4), 32 patients (9%) experienced HF events and 19 (5%) died suddenly or experienced aSCD. LV GLS was associated with HF events in a multivariable model when considered as either a continuous (per % hazard ratio [HR] 1.10, 95% confidence interval [CI] 1.00–1.21, p = 0.045) or dichotomized variable (LV GLS > −15.4%: HR 2.70, 95% CI 1.30–5.94, p = 0.008). LGE presence was not associated with HF events (HR 1.49, 95% CI 0.73–3.01, p = 0.270). Conversely, LV GLS was not associated with SCD/aSCD (per % HR 1.07, 95% CI 0.95–1.22, p = 0.257), whereas LGE presence was (HR 3.58, 95% CI 1.39–9.23, p = 0.008). LVEF was neither associated with HF events nor SCD/aSCD.Multi‐parametric CMR has utility for precision prognostic stratification of patients with DCMmrEF. LV GLS stratifies risk of progressive HF, while LGE stratifies SCD risk. [ABSTRACT FROM AUTHOR]

Summary: This analysis investigated the incidence of sudden deaths (SDs) and non‐fatal and fatal ventricular arrhythmias (VAs) in five acalabrutinib clinical trials. In total, 1299 patients received acalabrutinib (exposure, 4568.4 patient‐years). Sixteen (1.2%) patients experienced SD or VA (event rate, 0.350/100 patient‐years). Non‐fatal VAs occurred in 11 (0.8%) patients, nine (0.7%) of whom had premature ventricular contractions only. SD and fatal VAs occurred in five (0.4%) patients (event rate, 0.109/100 patient‐years; median time to event: 46.2 months). SDs and VAs with acalabrutinib occurred at low rates, and there are insufficient data to point to an increased risk of SD or VA with acalabrutinib. [ABSTRACT FROM AUTHOR]

Aim: Cardiac arrhythmias are among the most important pathologies that cause sudden death. The exploration of new therapeutic options against arrhythmias with low undesirable effects is of paramount importance. Methods: However, the convenient and typical animal model for screening the potential lead compound becomes a very critical modality, particularly in anti-arrhythmia. In this study, mice were intraperitoneally (i.p.) injected with BaCl2, CaCl2, and adrenaline to induce arrhythmia, and simultaneously compared with BaCl2-induced rats. Results: Electrocardiogram (ECG) showed that the majority of mice repeatedly developed ventricular bigeminy, ventricular tachycardia (VT), and ventricular fibrillation (VF) after BaCl2-injection as seen in rats. The ECG of mice developed ventricular bigeminy and VT after CaCl2 and AT after adrenaline i.p. injection. Additionally, acute cardiac arrhythmia after BaCl2 i.p. injection could be reverted by drugs (lidocaine and amiodarone) administration. Additionally, the different routes of administration for various chemical-induced arrhythmia in both mice and rats were also retrieved from PubMed and summarized. Comparing this approach with previous studies after the literature review reveals that arrhythmia of BaCl2-induced i.p. mice is compatible with the induction of other routes. Conclusions: This study brings an alternative experimental model to investigate antiarrhythmic theories and provides a promising approach to discovering new interventions for acute arrhythmias. [ABSTRACT FROM AUTHOR]

Background: Implantable cardioverter defibrillators (ICD) prevent sudden cardiac death (SCD). Patients with end-stage renal disease (ESRD) requiring dialysis are at a very high risk of infection from cardiac implantable electronic device (CIED) implantation as well as mortality. In the present study, we compared the long-term complications and outcomes between subcutaneous ICD (S-ICD) and transvenous ICD (TV-ICD) recipients. Methods: In this retrospective analysis, we analyzed a total of 43 patients with ESRD requiring dialysis who received either a prophylactic S-ICD (26 patients) or a single right ventricular lead TV-ICD (17 patients) at seven experienced centers in Germany. Follow-up was performed bi-annually, at the end of which the data concerning comorbidities and, if applicable, reason for death were checked and confirmed with patients' general practitioner, nephrologist and cardiologist. Results: The median follow up duration was 95.6 months (range 42.8–126.3 months). Baseline characteristics were without noteworthy significant differences between groups. During follow-up (FU), there were significantly more device-associated infections (HR 8.72, 95% confidence interval (CI), 1.18 to 12.85, p < 0.05) and device-associated hospitalizations (HR 10.20, 95% CI 1.22 to 84.61, p < 0.001), as well as a higher cardiovascular mortality (HR 9.17, 95% CI 1.12 to 8.33, p < 0.05), in the TV-ICD group. The number of patients requiring hospitalization for any reason was significantly higher in the TV-ICD group (HR 2.59, 95% CI 1.12 to 6.41, p < 0.05). There was no significant difference in overall mortality (HR 1.92, 95% CI 0.96 to 6.15, p = 0.274). Conclusions: Our data suggest that, in this extended follow-up in seriously compromised renal patients on dialysis, the S-ICD patients have statistically fewer device infections and hospitalizations as well as lower cardiac mortality compared with the TV-ICD cohort. [ABSTRACT FROM AUTHOR]

Williams–Beuren syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multisystem disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis (SVAS). Those with WBS are at increased risk of sudden death, but mechanisms underlying this remain poorly understood. We recently demonstrated autonomic abnormalities in those with WBS that are associated with increased susceptibility to arrhythmia and sudden cardiac death (SCD). A recently introduced method for heart rate variability (HRV) analysis called "heart rate fragmentation" (HRF) correlates with adverse cardiovascular events (CVEs) and death in studies where heart rate variability (HRV) failed to identify high-risk subjects. Some argue that HRF quantifies nonautonomic cardiovascular modulators. We, therefore, sought to apply HRF analysis to a WBS cohort to determine 1) if those with WBS show differences in HRF compared with healthy controls and 2) if HRF helps characterize HRV abnormalities in those with WBS. Similar to studies of those with coronary artery disease (CAD) and atherosclerosis, we found significantly higher HRF (4 out of 7 metrics) in those with WBS compared with healthy controls. Multivariable analyses showed a weak-to-moderate association between HRF and HRV, suggesting that HRF may reflect HRV characteristics not fully captured by traditional HRV metrics (autonomic markers). We also introduce a new metric inspired by HRF methodology, significant acute rate drop (SARD), which may detect vagal activity more directly. HRF and SARD may improve on traditional HRV measures to identify those at greatest risk for SCD both in those with WBS and in other populations. NEW & NOTEWORTHY: This work is the first to apply heart rate fragmentation analyses to individuals with Williams syndrome and posits that the heart rate fragmentation parameter W3 may enable detection and investigation of phenomena underlying the proarrhythmic short-long-short RR interval sequences paradigm known to precede ventricular fibrillation and ventricular tachycardia. It also forwards a novel method for quantifying sinus arrhythmia and sinus pauses that likely correlate with parasympathetic activity. [ABSTRACT FROM AUTHOR]

A four-year-old Labrador Retriever was presented for intermittent tachycardia. The electrocardiogram showed sinus rhythm conducted with ventricular pre-excitation and short runs of orthodromic atrioventricular reciprocating tachycardia. Four months later, the rhythm degenerated into a symptomatic sustained tachycardia, suspected to be pre-excited atrial fibrillation, a potentially life-threatening rhythm in the presence of an accessory pathway with a short refractory period. Two days after initiating oral diltiazem, the dog deteriorated and represented with sustained orthodromic atrioventricular reciprocating tachycardia, which was terminated by a precordial chest thump. It proceeded to sinus rhythm with ventricular pre-excitation followed by an episode of pre-excited focal atrial tachycardia. A bolus of lidocaine IV successfully restored sinus rhythm and sotalol treatment was started. The dog clinically recovered but died spontaneously 24 h later. This is the first case report that describes spontaneous pre-excited focal atrial tachycardia. [ABSTRACT FROM AUTHOR]

Out‐of‐hospital cardiac arrest (OHCA) is a global public health problem, with survival rates remaining low at around 10% or less despite widespread cardiopulmonary resuscitation (CPR) training and availability of automated external defibrillators (AEDs). This is partly due to the challenges of knowing when and where a sudden OHCA occurs and where the nearest AED is located. In response, countries around the world have begun to use network technology‐based smartphone applications. These applications are activated by emergency medical service dispatchers and alert preregistered volunteer first responders (VFRs) to nearby OHCAs using Global Positioning System localization. Accumulating evidence, although mostly from observational studies, shows their effectiveness in increasing the rate of bystander CPR, defibrillation, and patient survival. Current guidelines recommend the use of these VFR alerting systems, and the results of ongoing randomized trials are awaited for further dissemination. This article also proposed the concept of a life‐saving mobile network (LMN), which uses opportunistic network and wireless sensor network technologies to create a dynamic mesh network of potential victims, rescuers, and defibrillators. The LMN works by detecting a fatal arrhythmia with a wearable sensor device, localizing the victim and the nearest AED with nearby smartphones, and notifying VFRs through peer‐to‐peer communication. While there are challenges and limitations to implementing the LMN in society, this innovative network technology would reduce the tragedy of sudden cardiac death from OHCA. [ABSTRACT FROM AUTHOR]

Background: Ventricular tachycardia (VT) remains a risk in repaired Tetralogy of Fallot (rTOF); however, long‐term benefits of VT ablation have not been established. This study compares the outcomes of rTOF patients with and without VT ablation. Methods: We searched multiple databases examining the outcomes of rTOF patients who had undergone VT ablation compared to those without ablation. Primary outcomes were VT recurrence, sudden cardiac death (SCD), and all‐cause mortality. Subgroup analysis was conducted based on the type of ablation (catheter and surgical). Slow‐conducting anatomical isthmus (SCAI)‐based catheter ablation (CA) was also analyzed separately. The secondary outcome was the risk factors for the pre‐ablation history of VT. Results: Fifteen cohort studies with 1459 patients were included, 21.4% exhibited VTs. SCAI was found in 30.4% of the population, with 3.7% of non‐inducible VT. Factors significantly associated with VT before ablation included a history of ventriculostomy, QRS duration ≥180 ms, fragmented QRS, moderate to severe pulmonary regurgitation, high premature ventricular contractions burden, late gadolinium enhancement, and SCAI. Ablation was only beneficial in reducing VTs recurrence in SCAI‐based CA (risk ratio (RR) 0.11; 95% CI 0.03 to 0.33. p < 0.001; I2 = 0%) with no recurrence in patients with preventive ablation (mean follow‐up time 91.14 ± 77.81 months). The outcomes of VT ablation indicated a favorable trend concerning SCD and all‐cause mortality (RR 0.49 and 0.44, respectively); however, they were statistically insignificant. Conclusions: SCAI‐based CA has significant advantages in reducing VT recurrence in rTOF patients. Risk stratification plays a key role in determining the decision to perform ablation. [ABSTRACT FROM AUTHOR]

Patients with hypertrophic cardiomyopathy (HCM) are at risk of sudden death, and individuals with ≥1 major risk markers are considered for primary prevention implantable cardioverter-defibrillators. Guidelines recommend cardiac magnetic resonance (CMR) imaging to identify high-risk imaging features. However, CMR imaging is resource intensive and is not widely accessible worldwide. The purpose of this study was to develop electrocardiogram (ECG) deep-learning (DL) models for the identification of patients with HCM and high-risk imaging features. Patients with HCM evaluated at Tufts Medical Center (N = 1930; Boston, MA) were used to develop ECG-DL models for the prediction of high-risk imaging features: systolic dysfunction, massive hypertrophy (≥30 mm), apical aneurysm, and extensive late gadolinium enhancement. ECG-DL models were externally validated in a cohort of patients with HCM from the Amrita Hospital HCM Center (N = 233; Kochi, India). ECG-DL models reliably identified high-risk features (systolic dysfunction, massive hypertrophy, apical aneurysm, and extensive late gadolinium enhancement) during holdout testing (c-statistic 0.72, 0.83, 0.93, and 0.76) and external validation (c-statistic 0.71, 0.76, 0.91, and 0.68). A hypothetical screening strategy using echocardiography combined with ECG-DL–guided selective CMR use demonstrated a sensitivity of 97% for identifying patients with high-risk features while reducing the number of recommended CMRs by 61%. The negative predictive value with this screening strategy for the absence of high-risk features in patients without ECG-DL recommendation for CMR was 99.5%. In HCM, novel ECG-DL models reliably identified patients with high-risk imaging features while offering the potential to reduce CMR testing requirements in underresourced areas. [Display omitted] [ABSTRACT FROM AUTHOR]

Background The notion that the 'interarterial' segment of anomalous aortic origin of a coronary artery (AAOCA) is 'malignant' and 'scissor-like' compressed between the aorta and pulmonary artery (PA) is debated, owing to the lower pressure in the pulmonary system compared with that in the coronary system. However, data supporting or refuting this belief under stress conditions are lacking. Case summary Three cases of right AAOCA with interarterial/intramural courses (52, 66, and 51 years old) were assessed. Invasively measured fractional flow reserve (FFR) under dobutamine was 0.85, 0.82, and 0.81, respectively. Intravascular ultrasound illustrated lateral vessel compression of the intramural course with a decrease of minimal lumen area (MLA) (i.e. 5.71–3.47 mm2, 5.88–4.00 mm2, and 5.85–4.06 mm2) under stress conditions with heart rates of 130, 140, and 150 b.p.m. respectively. Pulmonary artery pressure (PAP) increased from rest {s/d (m) [systolic/diastolic (mean)] 22/11 (15), 15/2 (5), and 24/6 (14) mmHg} to stress [s/d (m) 47/24 (36), 30/3 (11), and 36/22 (24) mmHg] and remained below aortic peak pressure (blood pressure, BP) rest [s/d (m) 116/64 (91), 94/48 (71), 99/53 and (62) mmHg]; BP stress [s/d (m) 142/63 (80), 123/63 (88), and 86/46 (62) mmHg]; coronary pressure (CoP) rest [s/d (m) 100/59 (80), 80/45 (62), and 83/47 (63) mmHg]; and CoP stress [s/d (m) 95/60 (69),101/54 (72), and 70/32 (50) mmHg]. Conclusion This case series challenges the assumption that the interarterial segment of AAOCA is scissor-like compressed by both the aorta and PA. The decrease in MLA and FFR under stress is due to the aorta's unidirectional lateral compression on the intramural segment. Additionally, the term 'malignant' should not be universally applied to all AAOCA cases with an interarterial course, as not all result in haemodynamic significance. [ABSTRACT FROM AUTHOR]

Background Arrhythmic mitral valve prolapse syndrome (ARMV) is a recognized but underdiagnosed disease pattern. Risk factors for ARMV are established but not very well known, and the association of the structural abnormality with ventricular arrhythmias is incompletely understood. Case summary Here, we present the case of a young man who presented at our hospital for radiofrequency catheter ablation and mitral valve surgery after two episodes of survived sudden cardiac arrest. We discuss the diagnostic and therapeutic strategies that were used. We shine light on the risk factors for ARMV and why early identification is crucial. We address the topic of primary prevention and its limitations. Finally, we discuss different treatment modalities for patients with ARMV. Discussion More awareness for ARMV is crucial. A consensus statement on clinical management exists, but scientific gaps in prospective data for primary prevention need to be filled and there is a need for a better understanding of the pathogenesis of ARMV. [ABSTRACT FROM AUTHOR]

Idiopathic ventricular fibrillation is diagnosed in survivors of sudden cardiac death that has been caused by ventricular fibrillation without known structural or electrical abnormalities, even after extensive investigation. It is a common cause of sudden death in young adults. Although idiopathic ventricular fibrillation is a diagnosis of exclusion, in many cases only a partial investigation algorithm is performed. The aim of this review is to present a comprehensive diagnostic evaluation algorithm with a focus on diagnostic assessment of inherited arrhythmic syndromes and genetic background. [ABSTRACT FROM AUTHOR]

Background: Sudden cardiac death (SCD) is a major public health concern worldwide, affecting all age and social groups. Methods: In this retrospective study, of the 8265 autopsies performed in the Institute of Legal Medicine, 1618 cases of SCD were included. The aim of this study is to identify demographic characteristics, etiological factors, epidemiological characteristics and risk factors that lead to SCD. Results: The highest incidence of SCD was in age group 40–69 years (65.0%), 71.6% of this age group being men. Of the total number, 32.1% (520) occurred in the emergency room. The most common cause of sudden death is represented by coronary atherosclerotic disease, reported in 89.8% (1453) of cases, tricoronary lesions being found in 60% (870) of cases. Etiological factors of SCD encountered during autopsies were acute myocardial infarction in 13.9% (225), dilated cardiomyopathy 43.9% (710), cardiac hypertrophy 579 (36.07%), pericarditis 1.9% (30), myocarditis 1.73% (28) and adipositas cordis 5% (81). Along with epicardial fat and BMI, alcohol consumption was recorded in 17.9% (290), this being a potential trigger. Conclusions: Based on forensic autopsy and histological findings, a wide variety of factors are involved in the etiopathogenesis of SCD, some of which can be eliminated through preventive measures implemented early. [ABSTRACT FROM AUTHOR]

Background and Aims Risk scores are proposed for genetic arrhythmias. Having proposed in 2010 one such score (M-FACT) for the long QT syndrome (LQTS), this study aims to test whether adherence to its suggestions would be appropriate. Methods LQT1/2/3 and genotype-negative patients without aborted cardiac arrest (ACA) before diagnosis or cardiac events (CEs) below age 1 were included in the study, focusing on an M-FACT score ≥2 (intermediate/high risk), either at presentation (static) or during follow-up (dynamic), previously associated with 40% risk of implantable cardioverter defibrillator (ICD) shocks within 4 years. Results Overall, 946 patients (26 ± 19 years at diagnosis, 51% female) were included. Beta-blocker (βB) therapy in 94% of them reduced the rate of those with a QTc ≥500 ms from 18% to 12% (P <.001). During 7 ± 6 years of follow-up, none died; 4% had CEs, including 0.4% with ACA. A static M-FACT ≥2 was present in 110 patients, of whom 106 received βBs. In 49/106 patients with persistent dynamic M-FACT ≥2, further therapeutic optimization (left cardiac sympathetic denervation in 55%, mexiletine in 31%, and ICD at 27%) resulted in just 7 (14%) patients with CEs (no ACA), with no CEs in the remaining 57. Additionally, 32 patients developed a dynamic M-FACT ≥2 but, after therapeutic optimization, only 3 (9%) had C Es. According to an M-FACT score ≥2, a total of 142 patients should have received an ICD, but only 22/142 (15%) were implanted, with shocks reported in 3. Conclusions Beta-blockers often shorten QTc, thus changing risk scores and ICD indications for primary prevention. Yearly risk reassessment with therapy optimization leads to fewer ICD implants (3%) without increasing life-threatening events. [ABSTRACT FROM AUTHOR]

Background: Inherited cardiomyopathies (HCM, DCM, ACM) and cardiac ion channelopathies (long QT/Brugada syndromes, CPVT) are associated with significant morbidity and mortality; however, diagnosis of a familial pathogenic variant in a proband allows for subsequent cascade screening of their at-risk relatives. Aims: We investigated the diagnostic yield from cardiac gene panel testing and reviewed variants of uncertain significance from patients attending three specialist cardiogenetics services in Ireland in the years 2002 to 2020. Results: Reviewing molecular genetic diagnostic reports of 834 patients from 820 families, the initial diagnostic yield of pathogenic/likely pathogenic variants was 237/834 patients (28.4%), increasing to 276/834 patients (33.1%) following re-evaluation of cases with variant(s) of uncertain significance. Altogether, 42/85 patients with VUS reviewed (49.4%) had a re-classification that could change their clinical management. Females were more likely to carry pathogenic/likely pathogenic variants than males (139/374, 37.2% vs 137/460, 29.8%, respectively, p = 0.03), and the diagnostic yields were highest in the 0 to < 2 years age group (6/12, 50.0%) and amongst those tested for cardiomyopathy gene panels (13/35, 37.1%). Variants in the MYBPC3/MYH7 (87/109, 79.8%) and KCNQ1/KCNH2 (91/100, 91.0%) genes were the predominant genetic causes for hypertrophic cardiomyopathy and long QT syndrome, respectively. Conclusion: Our study highlights the importance of collation and review of pre-ACMG genetic variants to increase diagnostic utility of genetic testing for inherited heart disease. Almost half of patients with pre-ACMG VUS reviewed had their variant re-classified to likely pathogenic/likely benign which resulted in a positive clinical impact for patients and their families. [ABSTRACT FROM AUTHOR]

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Obesity condition causes morphological and functional alterations involving the cardiovascular system. These can represent the substrates for different cardiovascular diseases, such as atrial fibrillation, coronary artery disease, sudden cardiac death, and heart failure (HF) with both preserved ejection fraction (EF) and reduced EF. Different pathogenetic mechanisms may help to explain the association between obesity and HF including left ventricular remodelling and epicardial fat accumulation, endothelial dysfunction, and coronary microvascular dysfunction. Multi‐imaging modalities are required for appropriate recognition of subclinical systolic dysfunction typically associated with obesity, with echocardiography being the most cost‐effective technique. Therapeutic approach in patients with obesity and HF is challenging, particularly regarding patients with preserved EF in which few strategies with high level of evidence are available. Weight loss is of extreme importance in patients with obesity and HF, being a primary therapeutic intervention. Sodium–glucose co‐transporter‐2 inhibitors have been recently introduced as a novel tool in the management of HF patients. The present review aims at analysing the most recent studies supporting pathogenesis, diagnosis, and management in patients with obesity and HF. [ABSTRACT FROM AUTHOR]

Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell–cell adhesion, cardiomyocyte death and fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-β have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy of autopsied human hearts. Our results showed 697 differentially expressed genes and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathways and inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of the miRNA–mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis, highlighting their value as potential key targets for therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: The association between opioid use and the risk of ventricular arrhythmias (VA) is poorly understood. Aims: The objective of this study was to synthesize the evidence on the risk of VA associated with opioid use. Materials & Methods: We systematically searched the Cochrane Library, Embase, MEDLINE, and CINAHL databases in July 2022. Risk of bias was assessed using the Cochrane risk for bias tool for randomized controlled trials (RCTs) and ROBINS‐I for observational studies. Certainty of evidence was assessed using GRADE. Results: We included 15 studies (12 observational, 2 post hoc analyses of RCTs, 1 RCT). Most studies focused on opioid use for maintenance therapy (n = 9), comparing methadone to buprenorphine (n = 13), and reported QTc prolongation (n = 13). Six observational studies had a critical risk of bias, and one RCT was at high risk of bias. Two studies could not be included in the meta‐analysis as they reported a different outcome and studied an opioid antagonist. Meta‐analysis of 13 studies indicated that the use of methadone was associated with an increased risk of VA compared to the use of buprenorphine, morphine, placebo, or levacetylmethadol (risk ratio [RR], 2.39; 95% CI, 1.31–4.35; I2 = 60%). The pooled estimate varied greatly between observational studies (RR, 2.12; 95% CI, 1.15–3.91; I2 = 62%) and RCTs (RR, 14.09; 95% CI, 1.52–130.61; I2 = 0%), but both indicated an increased risk. Conclusion: In this systematic review and meta‐analysis, we found that methadone use is associated with more than twice the risk of VA compared to comparators. However, our findings should be interpreted cautiously given the limited quality of the available evidence. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusions The programing of subcutaneous implantable cardioverter‐defibrillators (S‐ICD) in clinical practice has been little studied, as the activation status of the SMART Pass filter, which was implemented to reduce inappropriate shocks.We assessed device programing during follow‐up and the rate of detected arrhythmias in consecutive S‐ICD recipients.We analyzed data from 670 S‐ICD patients followed on the remote network at 17 Italian centers for a median of 31 months (25th–75th percentile: 16–51). The enhanced SMART Pass version, introduced in October 2022, was expected to reduce the unintentional deactivation rate.At the latest remote data transmission, the median conditional zone cut‐off was set to 210 bpm (25th–75th percentile: 200–220), the shock zone cutoff was 250 bpm (25th–75th percentile: 240–250), and the SMART Pass was enabled in 586 (87%) patients. During follow‐up, 194 automatic deactivation events were reported in 118 (18%) patients. Shocks were delivered in 129 (19%) patients, and untreated arrhythmias were recorded in 136 (20%) patients. The rate of shocks was lower when SMART Pass was enabled ‐0.12/patient‐year (95% CI: 0.10–0.14) versus 0.20 (95% CI: 0.15–0.26) (p = .002), as it was the rate of untreated arrhythmias ‐0.12/patient‐year (95% CI: 0.11–0.14) versus 0.23 (95% CI: 0.18–0.30) (p = .001). The enhanced SMART Pass version was associated with a lower rate of deactivations ‐0.04/patient‐year (95% CI: 0.02–0.05) versus 0.14 (95% CI: 0.12–0.16) (p < .001), and with a reduction in treated and untreated arrhythmias (Incidence rate ratios: 0.40 (95% CI: 0.28–0.53) and 0.40 (95% CI: 0.30–0.55), respectively (p < .001)).Centers tend to program devices to detect high ventricular rates for arrhythmia detection, to minimize inappropriate shock occurrences. SMART Pass activation is associated with lower rates of detected and treated arrhythmias. The enhanced SMART Pass version seems associated with a lower deactivation rate and with a further decrease in treated arrhythmias. [ABSTRACT FROM AUTHOR]